Immunotherapy is evolving to become established as a potent therapeutic modality for the treatment of multiple cancer types. Notably in melanoma, but also in other cancer entities including lung cancer, head and neck cancer and breast cancer, it has become increasingly apparent that a subset of tumors demonstrates the presence of tumor-reactive T cells present within the tumor microenvironment, while others lack such an infiltrate. The absence of an anti-tumor immune response within the tumor microenvironment recently has been correlated with the lack of responsiveness against immunotherapies, including anti-PD-1. Thus, identifying the molecular mechanisms causing the lack of T cell infiltration will be crucial for expanding the clinical efficacy of immunotherapies. Recent work from our laboratory has identified tumor-cell intrinsic Wnt/?- catenin signaling as a potential cause for the lack of an anti-tumor T cell infiltrate in malignant melanoma. Using patient material, we identified a correlation between lack of a T cell-gene signature and enhanced ?- catenin target genes. Using an inducible autochthonous mouse model, we showed that suppression of dendritic cell-attracting chemokines was directly mediated by ?-catenin signaling, resulting in a lack of tumor- infiltrating dendritic cells. The deficiency in dendritic cells was directly correlated with a lack of T cell activation and failed T cell recruitment. Based on these observations we hypothesize that tumor cell-intrinsic activation of specific oncogenic pathways determine the composition of the tumor microenvironment and directly impact the anti-tumor immune response. To test this hypothesis we propose: (1) to evaluate whether tumor-intrinsic ?-catenin activation mediates resistance to an expanded effector T cell population and adoptive T cell therapy; (2) to develop novel treatment strategies to generate a T cell-attracting tumor microenvironment; (3) to determine whether activation of additional oncogenic pathways can mediate immune exclusion from the tumor microenvironment; and (4) to interrogate if the activation of the Wnt/?-catenin pathway is associated with T cell exclusion in cancer types beyond melanoma. The proposed studies aim to elucidate key mechanistic event in tumor escape from host immunity, and therefore will provide highly important insights in the interplay between a growing tumor and the immune system. Furthermore, understanding the basic mechanisms will be the first step in achieving the overarching translational goal to reverse T cell exclusion in patients, thus expanding the fraction of patients showing clinical benefit to immunotherapeutic interventions.